Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma

ABSTRACT

The use of inhibitors of GSK-3 useful for treating glaucoma is disclosed.

[0001] The present invention is directed to inhibitors of glycogensynthase kinase-3 for lowering and controlling normal or elevatedintraocular pressure (IOP) and treating glaucoma.

BACKGROUND OF THE INVENTION

[0002] The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. The several morphologically or functionally distinct typesof glaucoma are typically characterized by elevated IOP, which isconsidered to be causally related to the pathological course of thedisease. Ocular hypertension is a condition wherein intraocular pressureis elevated, but no apparent loss of visual function has occurred; suchpatients are considered to be a high risk for the eventual developmentof the visual loss associated with glaucoma. Some patients withglaucomatous field loss have relatively low intraocular pressure. Theseso called normotension or low tension glaucoma patients can also benefitfrom agents that lower and control IOP. If glaucoma or ocularhypertension is detected early and treated promptly with medicationsthat effectively reduce elevated intraocular pressure, loss of visualfunction or its progressive deterioration can generally be ameliorated.Drug therapies that have proven to be effective for the reduction ofintraocular pressure include both agents that decrease aqueous humorproduction and agents that increase the outflow facility. Such therapiesare in general administered by one of two possible routes, topically(direct application to the eye) or orally.

[0003] There are some individuals who do not respond well when treatedwith certain existing glaucoma therapies. There is, therefore, a needfor other topical therapeutic agents that control IOP.

SUMMARY OF THE INVENTION

[0004] The present invention is directed to inhibitors of GSK-3 whichcan be used to treat glaucomatous optic neuropathy and/or lower andcontrol IOP associated with normal-tension glaucoma, ocularhypertension, and/or glaucoma in warm blooded animals, including man.The compounds are formulated in pharmaceutical compositions suitable fortopical delivery to the eye.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Elevated intraocular pressure (IOP) is often an indicator ofglaucoma. Left unchecked, continual and long term elevated IOP cancontribute to the progressive deterioration of the retina and the lossof visual function. Therefore, lowering IOP is often an objective in thetreatment of glaucoma patients in order to decrease the potential for orseverity of glaucomatous retinopathy. It has been shown that even thoseglaucoma patients who do not exhibit elevated levels of IOP benefit fromagents that lower and control IOP. Unfortunately, some individuals donot respond well when treated with certain existing glaucoma therapies.

[0006] Wnt proteins comprise a large family of structurally relatedligands that activate the Wnt signaling pathway. The frizzle family ofproteins are key components in this pathway serving as membrane boundreceptors for Wnt. The frizzle proteins are a family of seventransmembrane proteins that have an N-terminal extracelluar cysteinerich domain and a cytoplasmic carboxylate tail. Binding of Wnt tofrizzle initiates a cascade of events one of which results in theinhibition of (GSK-3) preventing the phosphorylation of β-catenin.Phosphorylation of β-catenin leads to its degradation. Activation of theWnt pathway increases the intracellular concentration of uncomplexedβ-catenin which can activate β-catenin-T cell factor/Lymphoid enhancerfactor (TCF/Lef) dependent gene transcription.

[0007] Frizzle Related Proteins (FRP) are a family of secreted proteinswith cysteine rich regions that are homologous to those of the frizzlefamily of proteins but lack the membrane-spanning segments of thefrizzle proteins. The secreted FRP acts to antagonize the Wnt signalingpathway by binding extracelluar Wnt and preventing it from interactingwith frizzle proteins or by forming a nonfunctional complexes with thefrizzled receptor. Bafico et al. (1999).

[0008] Recently it has been discovered that frizzled related protein(FRP) is differentially expressed in a number of glaucomatous trabecularmeshwork cell lines. Perfusion of FRP-1 through perfused human ocularanterior segments maintained in culture resulted in a decrease inflowrate and a corresponding decrease in β-catenin protein levels in theciliary body and the trabecular meshwork (TM). The decreased flow ratein the cultured anterior segments models an increase in resistance tooutflow (increase in intraocular pressure) in intact eye. These resultsshow that there is an active Wnt signaling pathway in the TM and ciliarybody and suggest that this pathway is responsible at least in part formaintaining outflow through the TM and thereby controlling IOP.

[0009] Since the intracellular level of β-catenin is at least partiallyregulated by its phosphorylation by GSK-3, inhibition of GSK-3 resultsin the increase in uncomplexed soluble β-catenin irrespective of thelevels of FRP. GSK-3 inhibitors circumvent the FRP mediated antagonismof the Wnt signaling pathway caused by the elevated levels of FRP andcounteract the increase in outflow resistance that results from theincrease in production of FRP in individuals with glaucoma.

[0010] Increased expression of FRP was also detected in the retinas fromhuman donors having retinitis pigmentosa (RP). RP is a family ofdegenerative diseases that effect the photoreceptors and causesblindness. Since FRP stimulates apoptosis in neurons in vitro thepresence of elevated FRP suggests that FRP mediated disruption of Wntsignaling may be involved in retinal degeneration. Although glaucoma isthe selective loss of retinal ganglion cells and not photoreceptor cellstoxicity mediated by increased expression of FRP or by other mechanismgoverned by a GSK-3 mediated pathway may contribute to the loss ofretinal ganglion cells in glaucoma. Therefore GSK-3 inhibitors wouldtreat the loss of retinal ganglion and also reduce intraocular pressureby increasing aqueous humor outflow.

[0011] While not being bound by theory the inventors believe thatinhibition of GSK-3 will lower and control normal or elevatedintraocular pressure (IOP) and treat glaucomatous optic neuropathy.Compounds that act as GSK-3 inhibitors are well known and have shown avariety of utilities, primarily for disorders or conditions associatedwith diabetes, dementias such as Alzheimer's disease and manicdepression. U.S. Pat. No. 6,057,117 discloses the use of selectiveinhibitors of GSK-3 for the treatment of diseases that are mediated byGSK-3 activity including diabetes mellitus. WO 00/38675 discloses amethod of treatment of conditions associated with a need for theinhibition of GSK-3, such as diabetes, conditions associated withdiabetes, chronic neurodegenerative conditions including dementias suchas Alzheimer's disease, manic depression, mood disorders such asschizophrenia, neurotraumatic disorders such as acute stroke, hair lossand cancer. WO 00/21927 discloses certain pyrrole-2,5-dione derivativesthat are GSK-3 inhibitors for the treatment of diabetes, dementias suchas Alzheimer's disease and manic depression. WO 01/56567 describes2,4-dimainothiazole derivatives and their use as GSK-3 inhibitors, WO01/49709 describes peptide inhibitors of GSK-3, WO 01/47533 disclosesthe development of modulatory strategies for the treatment of variousdiseases. WO 01/41768 discloses the use of hymenialdisine or derivativesfor inhibiting cyclin dependent kinases, GSK-3 beta and casein kinase 1for treating neurodegenerative disorders such as Alzheimer's disease,diabetes, inflammatory pathologies and cancers. WO 01/37819 disclosesthe use of indirubine derivatives for making medicines inhibiting GSK-3beta.

[0012] Certain paullones analogs have been reported (Leost et al. 2000)to be GSK-3 inhibitors. These compounds were proposed to be useful inthe study and possible treatment of neurodegenerative and proliferativedisorders.

[0013] 3-Anilino-4-arylmaleimides have been reported to be potent andselective inhibitors of GSK-3 (Smith et al. 2001).

[0014] Hymenialdisine is an inhibitor of GSK-3. It was suggested to havepotential in treating neurodegenerative disorders (Thunnissen et al.2000).

[0015] The protein kinase C inhibitors GF1092 and Ro 31-8220 have beenreported to be inhibitors of GSK-3 (Tavare et al. 1999).

[0016] Indirubines inhibit GSK-3 (Garnier et al. 2001). A potentialapplication for the use of the indirubines as a treatment ofneurodegenerative disorders was disclosed.

[0017] GSK-3 inhibitors SB-415286 and SB216763 protected both centraland peripheral neurons grown in culture from death induced by reducedphosphatidyl inositol pathway activity (Cross et al. 2000).

[0018] The use of these compounds to lowering and controlling normal orelevated intraocular pressure (IOP) and to treat glaucoma has not beendisclosed.

[0019] This invention is directed at the treatment of glaucoma by theinhibition of GSK-3. It is contemplated that any GSK-3 inhibitingcompound will be useful in the methods of the present invention. Theinventors contemplate that any of the compounds disclosed in WO00/38675; WO 00/21927; Coglan et al. 2000; Leost et al. 2001; Smith etal. 2001; Garnier et al. 2001; Cross et al. 2001; Thunnissen et al.2000; Tavare et al. 1999 (as discussed above, all herein incorporated byreference) will be particularly useful.

[0020] In one preferred embodiment, the compound for use in the methodsof the invention will be selected from compounds defined in WO 00/21927,EP 470490, WO 93/18766, WO 93/18765, EP 397060, WO 98/11103, WO98/11102, WO 98/04552, WO 98/04551, DE 4243321, DE 4005970, DE 3914764,WO 96/04906, WO 95/07910, DE 4217964, U.S. Pat. No. 5,856,517, U.S. Pat.No. 5,891,901, WO 99/42100, EP 328026, EP 384349, EP 540956, DE 4005969,or EP 508792.

[0021] Preferred compounds include compounds of the formula:

[0022] wherein R¹ and R² independently=

[0023] R³═H, C₁₋₆alkyl, (un)substituted phenyl, C₁₋₆alkyl-NR⁶R⁷,C₁₋₇cycloalkyl, C₁₋₆alkyl-OR⁶, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷;

[0024] R⁴═H, or one or more substituents C₁₋₆alkyl, (un)substitutedphenyl, —OR⁶, —SR⁶, halogen, (un)substituted phenoxy, —CN, —NO₂,C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷, C₁₋₇cycloalkyl, (un)substituted heterocyclyl,—C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; and

[0025] R⁵, R⁶, R⁷═H, C₁₋₆alkyl, (un)substituted phenyl.

[0026] Preferably,

[0027] R¹=A, B; R²═B, C;

[0028] R³═H, C₁₋₆alkyl, C₁₋₆alkyl-NR⁶R⁷, C₁₋₆alkyl-OR⁶,C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷;

[0029] R⁴═H, or one or more substituents C₁₋₆alkyl, (un)substitutedphenyl, —OR⁶, halogen, (un)substituted phenoxy, —NO², C₁₋₆alkyl-NR⁶R⁷,—NR⁶R⁷, (un)substituted heterocyclyl, —C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵,C₁₋₆alkylC(O)NR⁶R⁷; and

[0030] R⁵, R⁶, R⁷═H, C₁₋₃alkyl.

[0031] The most preferred compounds for use in the methods of theinvention include:

[0032]3-(1-[3-aminopropyl]-3-indoyl)-4-(2-chlorophenyl)pyrrole-2,5-dione and

[0033]3-(1-[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.

[0034] In other embodiments, compounds useful in the methods of theinvention will be selected from the indirubine analogs defined in WO01/37819. Generally preferred compounds include indirubine,5-iodo-indirubine-3′monoxime, 5-(hydroxyethylsulfonamide)indirubine,indirubine-3′-monoxime, 5-(methyl)sulfonamide indirubine, and5-(dimethyl)sulfonamide indirubine.

[0035] Additional embodiments of the invention include the use ofcompounds selected from the 2,4-diaminothiazole analog defined in WO01/37819. Preferred compounds include:

[0036] (4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,

[0037] (4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,

[0038] (4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,

[0039] (4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,

[0040] 1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one

[0041] (4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,

[0042] (4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,

[0043] (4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,

[0044] (4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,

[0045] 4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,

[0046] [4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,

[0047] (4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,

[0048](4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,

[0049] (4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,

[0050] (4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,

[0051] (4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,

[0052](4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,

[0053] (4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,

[0054] (4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,

[0055] (4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,

[0056] (4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,

[0057] (4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,

[0058](4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,

[0059](4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,

[0060] 1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,

[0061] [4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,

[0062] [4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,

[0063][4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,

[0064] 3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acidethyl ester

[0065][4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,

[0066][4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,and

[0067] (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.

[0068] In still another embodiment, compounds selected from the1,2,4-triazole-carboxylic acid derivative or analog defined in WO01/09106 will be useful in the methods of the invention. Preferred1,2,4-triazole-carboxylic acid derivatives include:

[0069] 3-amino-5-anilino-2-benzoyl-1,2,4-triazole,

[0070] 3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,

[0071] 3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,

[0072] 3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,

[0073] 3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,

[0074] 3-amino-5-anilino-1,2,4-triazole-2-carboxylic acidcyclohexylamide,

[0075] 3-amino-5-anilino-1,2,4-triazole-1-carboxylic acidcyclohexylamide,

[0076] 3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,

[0077] 3-amino-5-anilino-2-(4-chlorobenzoyl)-1,2,4-triazole,

[0078] 3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,

[0079] 3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,

[0080] 3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,

[0081] 3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,

[0082] 3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole,

[0083] 3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,

[0084] 3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,

[0085] 3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,

[0086] 3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,

[0087] 3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,

[0088] 3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,

[0089] 3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,

[0090] 3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,

[0091] 3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,

[0092] 3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,

[0093] 3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,

[0094] 3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,

[0095] 3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,

[0096] 3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,

[0097]3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,

[0098] 3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,

[0099] 3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,

[0100]3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,

[0101] 3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid4-biphenylamide,

[0102] 3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-phenoxyphenyl)amide,

[0103] 3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-bromo-2-methylphenyl)amide,

[0104] 3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(1-naphthyl)amide,

[0105] 3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(3-methoxyphenyl)amide,

[0106] 3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylicacid(4-chlorophenyl)amide, and

[0107] 3,5-diamino2-benzoyl-1,2,4-triazole.

[0108] Hymenialdisine or derivative or analog defined in WO 01/41768 mayalso be useful in certain embodiments of the invention. Preferred suchcompounds include:

[0109]Hymenialdisine(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),

[0110]4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,and

[0111](4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.

[0112] Other embodiments of the invention include the use of paulloneanalogs, including 9-nitropaullone, 9-bromopaullone, 9-chloropaullone,and 9-bromo-12-methoxycarbonylmethypaullone in the methods of theinvention.

[0113] The Compounds of this invention, can be incorporated into varioustypes of ophthalmic formulations for delivery to the eye (e.g.,topically, intracamerally, or via an implant). The Compounds arepreferably incorporated into topical ophthalmic formulations fordelivery to the eye. The Compounds may be combined withophthalmologically acceptable preservatives, surfactants, viscosityenhancers, penetration enhancers, buffers, sodium chloride, and water toform an aqueous, sterile ophthalmic suspension or solution. Ophthalmicsolution formulations may be prepared by dissolving a Compound in aphysiologically acceptable isotonic aqueous buffer. Further, theophthalmic solution may include an ophthalmologically acceptablesurfactant to assist in dissolving the Compound. Furthermore, theophthalmic solution may contain an agent to increase viscosity, such as,hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to, gellan and xanthan gum. In order to prepare sterileophthalmic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the Compound in a hydrophilic base prepared fromthe combination of, for example, carbopol-974, or the like, according tothe published formulations for analogous ophthalmic preparations;preservatives and tonicity agents can be incorporated.

[0114] The Compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 4 to 8. The establishmentof a specific dosage regimen for each individual is left to thediscretion of the clinicians. The Compounds will normally be containedin these formulations in an amount 0.01% to 5% by weight, but preferablyin an amount of 0.05% to 2% and most preferably in an amount 0.1 to 1.0%by weight. The dosage form may be a solution, suspension microemulsion.Thus, for topical presentation 1 to 2 drops of these formulations wouldbe delivered to the surface of the eye 1 to 4 times per day according tothe discretion of a skilled clinician.

[0115] The Compounds can also be used in combination with other agentsfor treating glaucoma, such as, but not limited to, β-blockers,prostaglandins, carbonic anhydrase inhibitors, α₂ agonists, miotics, andneuroprotectants.

[0116] The following examples are representative of the techniquesemployed by the inventors in carrying out aspects of the presentinvention. It should be appreciated that while these techniques areexemplary of preferred embodiments for the practice of the invention,those of skill in the art, in light of the present disclosure, willrecognize that numerous modifications can be made without departing fromthe spirit and intended scope of the invention.

EXAMPLE 1 GSK-3 Inhibition

[0117] Inhibition of GSK-3 can be assayed by the methods described in WO00/38675. Compounds are evaluated for their ability to inhibit thephosphorylation of a biotinylated peptide derived from the peptidesequence for the phosphorylation site of glycogen synthase.Biot-KYRRAAVPPSPSLSRHSSPHQ(SP)EDEEE is used as the substrate peptidewhere (SP) is a prephosphorylated serine and S are the three consensusphosphorylation sites for GSK-3 specific phosphorylation. GSK-3 kinase(10 nM final concentration) in a pH 7.0 MOPS buffer containing Tween-200.01%, glycerol 5%, 2-mercaptoethanol 7.5 mM, magnesium acetate 10 mM,substrate peptide 8 μM, [γ-³³P]-ATP 10 μM and inhibitor are incubated atroom temperature for 1 hour. The reaction is stopped by the addition ofan aqueous mM EDTA solution containing Strepavidin coated SPA beads.Following centrifugation radioactivity is counted using a betascintillation counter.

EXAMPLE 2 Inhibition of the FRP Induced Reduction in Outflow Rate andβ-catenin Levels in Perfused Anterior Segments

[0118] Human ocular anterior segments are perfused with Dulbecco'smodified Eagle's medium (DMEM) at a constant pressure of 11 mm Hg. Theoutflow rate of each eye is measured by weighing its reservoir atspecified periods. After a stabilization period, the eyes are perfusedwith either vehicle or FRP-1 (10 μg/ml) and their outflow ratesmonitored for 2-5 days. The perfusion of FRP-1 caused a decrease inaqueous humor outflow. Inhibitor is added and the anterior segment isperfused for an additional 2-4 days. Outflow rate is measured byweighing its reservoir at specific periods.

EXAMPLE 3

[0119] Ingredients Amount (wt %) Compound of Example 1 0.01-2%**Hydroxypropyl methylcellulose  0.5% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride  0.5% Disodium EDTA (Edetate disodium) 0.01%Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4 Purified waterq.s. to 100%

EXAMPLE 4

[0120] Ingredients Amount (wt %) Compound of Example 1 0.01-2% Methylcellulose  4.0% Dibasic sodium phosphate (anhydrous)  0.2% Sodiumchloride  0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 800.05% Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

EXAMPLE 5

[0121] Ingredients Amount (wt %) Compound of Example 1 0.01-2% Guar gum 0.4-6.0%   Dibasic sodium phosphate (anhydrous)  0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05%Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

EXAMPLE 6

[0122] Ingredients Amount (wt %) Compound of Example 1 0.01-2% Whitepetrolatum and mineral oil and lanolin Ointment consistency Dibasicsodium phosphate (anhydrous)  0.2% Sodium chloride  0.5% Disodium EDTA(Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4

[0123] All of the compositions and/or methods disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure. While the compositions and methods of thisinvention have been described in terms of preferred embodiments, it willbe apparent to those of skill in the art that variations may be appliedto the compositions and/or methods and in the steps or in the sequenceof steps of the method described herein without departing from theconcept, spirit and scope of the invention. More specifically, it willbe apparent that certain agents which are both chemically andstructurally related may be substituted for the agents described hereinto achieve similar results. Such substitutions and modificationsapparent to those skilled in the art are deemed to be within the spirit,scope and concept of the invention as defined by is the appended claims.

[0124] References

[0125] The following references, to the extent that they provideexemplary procedural or other details supplementary to those set forthherein, are specifically incorporated herein by reference.

[0126] Patents

[0127] DE 3914764

[0128] DE 4005969

[0129] DE 4005970

[0130] DE 4217964

[0131] DE 4243321

[0132] EP 328026

[0133] EP 384349

[0134] EP 397060

[0135] EP 470490

[0136] EP 508792

[0137] EP 540956

[0138] U.S. Pat. No. 5,856,517

[0139] U.S. Pat. No. 5,891,901

[0140] U.S. Pat. No. 6,057,117

[0141] WO 93/18765

[0142] WO 93/18766

[0143] WO 95/07910

[0144] WO 96/04906

[0145] WO 98/04551

[0146] WO 98/04552

[0147] WO 98/11102

[0148] WO 98/11103

[0149] WO 99/42100

[0150] WO 00/21927

[0151] WO 00/38675

[0152] WO 01/09106

[0153] WO 01/37819

[0154] WO 01/41768

[0155] WO 01/47533

[0156] WO 01/49709

[0157] WO 01/56567

[0158] Other References

[0159] Bafico et al., J. BIOL. CHEM., 274(23):16180-16187 (1999)

[0160] Leost et al., EUR. J. BIOCHEM., 267:5983-5994 (2001)

[0161] Smith et al., BIOORGANIC & MED. CHEM. LETTERs, 11:635-639 (2001)

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We claim:
 1. A method for treating glaucomatous optic neuropathycomprising administrering to a patient in need thereof a therapeuticallyeffective amount of a composition comprising at least one glycogensynthase kinase-3 (GSK-3) inhibitor in a pharmaceutically acceptablecarrier.
 2. The method of claim 1, wherein said GSK-3 inhibitor is acompound of the formula:

wherein R¹ and R² independently=

R³═H, C₁₋₆alkyl, (un)substituted phenyl, C₁₋₆alkyl-NR⁶R⁷,C₁₋₇cycloalkyl, C₁₋₆alkyl-OR⁶, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷;R⁴═H, or one or more substituents C₁₋₆alkyl, (un)substituted phenyl,—OR⁶, —SR⁶, halogen, (un)substituted phenoxy, —CN, —NO₂,C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷, C₁₋₇cycloalkyl, (un)substituted heterocyclyl,—C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; and R⁵, R⁶, R⁷═H,C₁₋₆alkyl, (un)substituted phenyl.
 3. The method of claim 2, whereinR¹=A, B; R²═B, C; R³═H, C₁₋₆alkyl, C₁₋₆alkyl-NR⁶R⁷, C₁₋₆alkyl-OR⁶,C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; R⁴═H, or one or more substituentsC₁₋₆alkyl, (un)substituted phenyl, —OR⁶, halogen, (un)substitutedphenoxy, —NO₂, C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷, (un)substituted heterocyclyl,—C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; and R⁵, R⁶, R⁷═H,C₁₋₆alkyl.
 4. The method of claim 3, wherein said GSK-3 inhibitor is3-(1-[3-aminopropyl]-3-indoyl)-4-(2-chlorophenyl)pyrole-2,5-dione or3-(1-[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.5. The method of claim 1, wherein said GSK-3 inhibitor is a compoundselected from the group consisting of indirubine analogs,2,4-diaminothiazole analogs, 1,2,4-triazole-carboxylic acid derivativesor analogs, hymenialdesine or derivatives or analogs thereof, andpaullone analogs.
 6. The method of claim 5, wherein the GSK-3 inhibitoris an indirubine analog.
 7. The method of claim 6, wherein the indrubineanalog is selected from the group consisting of indirubine,5-iodo-indirubine-3′monoxime, 5-(hydroxyethylsulfonamide)indirubine,indirubine-3′-monoxime, 5-(methyl)sulfonamide indirubine, and5-(dimethyl)sulfonamide indirubine.
 8. The method of claim 5, whereinthe GSK-3 inhibitor is a 2,4-diaminothiazole analog.
 9. The method ofclaim 8, wherein the 2,4-diaminothiazole analog is selected from thegroup consisting of:(4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,(4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one(4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,(4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,(4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,[4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,[4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,[4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethylester[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,and (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.
 10. The method ofclaim 5, wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylic acidderivative or analog.
 11. The method of claim 10, wherein the1,2,4-triazole-carboxylic acid derivative or analog is selected from thegroup consisting of: 3-amino-5-anilino-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide,3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide,3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole,3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-phenoxyphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-bromo-2-methylphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(1-naphthyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(3-methoxyphenyl)amide,3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylicacid(4-chlorophenyl)amide, and 3,5-diamino2-benzoyl-1,2,4-triazole. 12.The method of claim 5, wherein the GSK-3 inhibitor is a hymenialdisinederivative or analog.
 13. The method of claim 12, wherein thehymenialdesine derivative or analog is selected from the groupconsisting of:Hymenialdisine(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,and(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.14. The method of claim 5, wherein the GKS-3 inhibitor is a paulloneanalog.
 15. The method of claim 14, wherein the paullone analog isselected from the group consisting of 9-nitropaullone, 9-bromopaullone,9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in themethods of the invention.
 16. The method of claim 1, wherein saidadministering is topical application, intracamerally or via an implant.17. The method of claim 1, wherein the concentration of said GSK-3inhibitor in said composition is from 0.01% to 2%.
 18. A method forlowering intraocular pressure (IOP) in a patient in need thereof saidmethod comprising administering to said patient a therapeuticallyeffective amount of a composition comprising at least one glycogensynthase kinase-3 (GSK-3) inhibitor in a pharmaceutically acceptablevehicle.
 19. The method of claim 18, wherein said GSK-3 inhibitor is acompound of the formula:

wherein R¹ and R² independently=

R³═H, C₁₋₆alkyl, (un)substituted phenyl, C₁₋₆alkyl-NR⁶R⁷,C₁₋₇cycloalkyl, C₁₋₆alkyl-OR⁶, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷;R⁴═H, or one or more substituents C₁₋₆alkyl, (un)substituted phenyl,—OR⁶, —SR⁶, halogen, (un)substituted phenoxy, —CN, —NO₂,C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷, C₁₋₇cycloalkyl, (un)substituted heterocyclyl,—C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; R⁵, R⁶, R⁷═H, C₁₋₆alkyl,(un)substituted phenyl.
 20. The method of claim 19, wherein R¹=A, B;R²═B, C; R³═H, C₁₋₆alkyl, C₁₋₆alkyl-NR⁶R⁷, C₁₋₆alkyl-OR⁶,C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; R⁴═H, or one or more substituentsC₁₋₆alkyl, (un)substituted phenyl, —OR⁶, halogen, (un)substitutedphenoxy, —NO₂, C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷, (un)substituted heterocyclyl,—C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; and R⁵, R⁶, R⁷═H,C₁₋₃alkyl.
 21. The method of claim 20, wherein said GSK-3 inhibitor is3-(1-[3-aminoprpyl]-3-indoyl)-4-(2-chlorophenyl)pyrole-2,5-dione or3-(1-[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.22. The method of claim 18, wherein said GSK-3 inhibitor is a compoundselected from the group consisting of indirubine analogs,2,4-diaminothiazole analogs, 1,2,4-triazole-carboxylic acid derivativesor analogs, hymenialdesine or derivatives or analogs thereof, andpaullone analogs.
 23. The method of claim 22, wherein the GSK-3inhibitor is an indirubine analog.
 24. The method of claim 23, whereinthe indrubine analog is selected from the group consisting ofindirubine, 5-iodo-indirubine-3′monoxime,5-(hydroxyethylsulfonamide)indirubine, indirubine-3′-monoxime,5-(methyl)sulfonamide indirubine, and 5-(dimethyl)sulfonamideindirubine.
 25. The method of claim 22, wherein the GSK-3 inhibitor is a2,4-diaminothiazole analog.
 26. The method of claim 25, wherein the2,4-diaminothiazole analog is selected from the group consisting of:(4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,(4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one(4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,(4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,(4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,[4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,[4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,[4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethylester[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,and (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.
 27. The method ofclaim 22, wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylicacid derivative or analog.
 28. The method of claim 27, wherein the1,2,4-triazole-carboxylic acid derivative or analog is selected from thegroup consisting of: 3-amino-5-anilino-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide,3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide,3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole,3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-phenoxyphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-bromo-2-methylphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(1-naphthyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(3-methoxyphenyl)amide,3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylicacid(4-chlorophenyl)amide, and 3,5-diamino2-benzoyl-1,2,4-triazole. 29.The method of claim 22, wherein the GSK-3 inhibitor is a hymenialdisinederivative or analog.
 30. The method of claim 29, wherein thehymenialdesine derivative or analog is selected from the groupconsisting of:Hymenialdisine(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,and(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.31. The method of claim 22, wherein the GKS-3 inhibitor is a paulloneanalog.
 32. The method of claim 31, wherein the paullone analog isselected from the group consisting of 9-nitropaullone, 9-bromopaullone,9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in themethods of the invention.
 33. The method of claim 18, wherein saidadministering is topical application, intracamerally or via an implant.34. The method of claim 18, wherein the concentration of said GSK-3inhibitor in said composition is from 0.01% to 2%.
 35. The method ofclaim 18, wherein said patient suffers from glaucoma or ocularhypertension.
 36. The method of claim 35, wherein said glaucoma isnormal-tension glaucoma.
 37. A method for preventing or inhibitingglaucomatous optic neuropathy and contolling IOP in a patient in needthereof, said method comprising at least one glycogen synthase kinase-3(GSK-3) inhibitor in a pharmaceutically acceptable carrier.
 38. Themethod of claim 37, wherein said GSK-3 inhibitor is a compound of the

formula: wherein R¹ and R² independently=A B C R³═H, C₁₋₆alkyl,(un)substituted phenyl, C₁₋₆alkyl-NR⁶R⁷, C₁₋₇cycloalkyl,

C₁₋₆alkyl-OR⁶, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; R⁴═H, or one ormore substituents C₁₋₆alkyl, (un)substituted phenyl, —OR⁶, —SR⁶,halogen, (un)substituted phenoxy, —CN, —NO₂, C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷,C₁₋₇cycloalkyl, (un)substituted heterocyclyl, —C(O)₂R⁵,C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; and R⁵, R⁶, R⁷═H, C₁₋₆alkyl,(un)substituted phenyl.
 39. The method of claim 38, wherein R¹=A, B;R²═B, C; R³═H, C₁₋₆alkyl, C₁₋₆alkyl-NR⁶R⁷, C₁₋₆alkyl-OR⁶,C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; R⁴═H, or one or more substituentsC₁₋₆alkyl, (un)substituted phenyl, —OR⁶, halogen, (un)substitutedphenoxy, —NO₂, C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷, (un)substituted heterocyclyl,—C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; and R⁵, R⁶, R⁷═H,C₁₋₃alkyl.
 40. The method of claim 39, wherein said GSK-3 inhibitor is3-(1-[3-aminoprpyl]-3-indoyl)-4-(2-chlorophenyl)pyrole-2,5-dione or3-(1-[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.41. The method of claim 37, wherein said GSK-3 inhibitor is a compoundselected from the group consisting of indirubine analogs,2,4-diaminothiazole analogs, 1,2,4-triazole-carboxylic acid derivativesor analogs, hymenialdesine or derivatives or analogs thereof, andpaullone analogs.
 42. The method of claim 41, wherein the GSK-3inhibitor is an indirubine analog.
 43. The method of claim 42, whereinthe indrubine analog is selected from the group consisting ofindirubine, 5-iodo-indirubine-3′monoxime,5-(hydroxyethylsulfonamide)indirubine, indirubine-3′-monoxime,5-(methyl)sulfonamide indirubine, and 5-(dimethyl)sulfonamideindirubine.
 44. The method of claim 41, wherein the GSK-3 inhibitor is a2,4-diaminothiazole analog.
 45. The method of claim 44, wherein the2,4-diaminothiazole analog is selected from the group consisting of:(4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,(4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one(4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,(4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,(4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,[4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,[4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,[4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethylester[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,and (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.
 46. The method ofclaim 41, wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylicacid derivative or analog.
 47. The method of claim 46, wherein the1,2,4-triazole-carboxylic acid derivative or analog is selected from thegroup consisting of: 3-amino-5-anilino-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide,3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide,3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole,3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-phenoxyphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(4-bromo-2-methylphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(1-naphthyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid(3-methoxyphenyl)amide,3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylicacid(4-chlorophenyl)amide, and 3,5-diamino2-benzoyl-1,2,4-triazole. 48.The method of claim 41, wherein the GSK-3 inhibitor is a hymenialdisinederivative or analog.
 49. The method of claim 48, wherein thehymenialdesine derivative or analog is selected from the groupconsisting of:Hymenialdisine(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,and(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.50. The method of claim 41, wherein the GKS-3 inhibitor is a paulloneanalog.
 51. The method of claim 50, wherein the paullone analog isselected from the group consisting of 9-nitropaullone, 9-bromopaullone,9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in themethods of the invention.
 52. The method of claim 37, wherein saidadministering is topical application, intracamerally or via an implant.53. The method of claim 37, wherein the concentration of said GSK-3inhibitor in said composition is from 0.01% to 2%.
 54. The method ofclaim 37, wherein said patient suffers from glaucoma or ocularhypertension.
 55. The method of claim 54, wherein said glaucoma isnormal-tension glaucoma.